towards implementing personalized al-mulla... · towards implementing personalized genomic medicine...

Towards implementing personalized genomic medicine in the Gulf States

Fahd Al-Mulla B.Sc., M.B.Ch.B., Ph.D. PCTM, FRCP

Professor of Molecular Pathology at Kuwait University Director of Genomic Medicine Center “GENATAK” Global Med Clinic ”جيناتك“

www.genatak.com

My talk www.genatak.com

• Introduce Kuwait and health service • Kuwait-specific public sector challenges • Brief History of our work and capabilities • The private sector model • Why Genome Arabia?

Area: Total: 17,820 sq km Population: Total: 3,442,945 Kuwaiti nationals: 1,102,485 Non-nationals : 2,340,460 (Public Authority of Civil Information, 2009 ) 6-Governorates Public and Private Hospitals Centralized specialized Free Health Service: -Kuwait Cancer Control Center -Kuwait Medical Genetics Center/maternity One public many private Universities

Kuwait www.genatak.com

• Research Administration office -Funding -Sets priorities -Outside Peer Reviews -Research records -Research Core Facilities -Patent and IP office -Focused on clinical research

Research and funding www.genatak.com

• Kuwait Foundation for the Advancement of Sciences. Directed Dr. Adnan Shihab Eldin

-1% of profit from local businesses -Research, programs and educational- based funding • Kuwait institute for Scientific research

another source of research Funding

Research and External funding www.genatak.com

http://kfas.org/index.html

• Nature 2006 issue on Islam and Science • Most Gulf sates spend 0.1-1% of GDP

towards research and development • Better trends now with Qatar 5% and

Saudi Arabia matching this and more • Kuwait-Bahrain-UAE-Oman remain on

low spending side

www.genatak.com Research funding a priority?

• Very difficult research environment • Delayed tenders/ethical approvals…. • Please read our cry for help in

theScientist

http://www.the-scientist.com/?articles.view/articleNo/29545/title/Another-Revolution-Needed-/

www.genatak.com Research barriers

www.genatak.com Convincing the Policymakers

• Since 2008-2012 • Demonstrate the effectiveness of GM for theranostics • Focus on Cost effectiveness?

Cost effective?

www.genatak.com

• Unknown • Current business model is flawed

- Benefit can be Lifelong - Involves additional modalities

• James M Crawford Personalized Medicine (2012) 9(3), 265–286

Cost effective? www.genatak.com

• Makes sense at individual/family level • Current cost to treat generation IV (M-

USD) • Personalized medicine potentially reduces

cost (K-USD)

Cost effective? Priceless! www.genatak.com

• Ashlyn Blocker • Channelopathy-associated Insensitivity to Pain (CIP) • Voltage-gated sodium channel Nav1.7 (SCN9A) gene truncating mutation

• IP value of blocking pain through Nav1.7

GM: shifting the paradigm www.genatak.com

Descriptive medicine

Empirical diagnosis

System/site based

Mechanistic medicine

Evidence-based diagnosis

Based on molecular classification

Uniform treatment

Acute care

Individualized therapy

Preventative and early detection

Genomic medicine: Evidence for Policymakers www.genatak.com

• Exome sequencing does not require

a priori knowledge of gene(s) responsible for a disorder

• Sikkema-Raddatz et al., demonstrated

that targeted NGS of a disease specific subset of genes is equal to the quality of Sanger sequencing and it can therefore be reliably implemented as a stand-alone diagnostic test.

Genomic medicine: What has changed? www.genatak.com

• 62 of the 250 patients (neurological

phenotype, unknown syndromes), achieving a 25% molecular diagnostic rate .

• Much higher than Sanger sequencing and microarrays

www.genatak.com

HOW HAS THIS CHANGED MEDICAL PRACTICE?

• Mutations associated with drug sensitivity: • EGFR Gly719X, exon 19 deletion,

Lue858Arg, Leu861Gln • Mutations associated with primary

drug resistance: • EGFR exon 20 insertions

• Mutations associated with acquired drug resistance: • EGFR Thr790Met, Asp761Tyr,

Leu747Ser, Thr854Ala

• Targeted exome approach

Genomic medicine: Evidence for Policymakers

Melanoma

www.genatak.com

• 38-year-old man with BRAF-mutant melanoma and miliary, subcutaneous metastatic deposits.

• A) before initiation of PLX4032 Vemurafenib • B) 15 weeks of therapy with PLX4032 • C) after 23 weeks of therapy • Relapse heterogeneity

Wagle N et al. JCO 2011;29:3085-3096

Genomic medicine: Evidence for Policymakers

Breast Cancer in Kuwait: Subtyping of breast cancer Prognostic breast cancer indices

Subtyping of Breast cancer

MamaPrint Oncotype PAM50 Nottingham index pro

Kuwait RKIP-based index

2333 cases

p < 0.0001

Normal-like Basal

Luminal-B

Claudin-low

Luminal-A

HER2+

Amplified untreated (n=110)

UnAmplified

Amplified and treated

n=111

P=0.001

P=0.001

Molecular Pathology (al-mulla.org) www.genatak.com

Discovery Loop

Study Genome

Discover variations

Study protein Proteomics

Functional studies Cell biology

Animal models

Translational Medicine

Patents Technology transfer

Spinoffs

United Kingdom National External Quality Assessment Service

Molecular Pathology (al-mulla.org) www.genatak.com

Top-to-bottom model www.genatak.com

No major reaction from policymakers Not reaching-out to the people/families Few doctors/specialists understood our GM

initiative No mechanism payment between hospitals

and University Health equity

Bottom-to-top Reach the people who need it

directly Limited bureaucracy Genatak (Arabic for your genes) Global Med Clinic houses major

specialties: Primary care, cardiology, pediatrics,….under the license of Dr. Jamal Al-Ghanim…and now personalized genomic medicine to serve all

GM and the private sector www.genatak.com

Genatak is part of a large world-wide network of laboratories that collectively offer highly specialized 2000 genetic tests

Access to 11 NGS instruments The network laboratories are

accredited by various agencies like CPA, CAP and CLIA and follow stringent quality assurance programs.

The laboratory network offers genetic counseling services

Genatak Laboratory Network www.genatak.com

What do we do? www.genatak.com

1. Genetic Disorders and Counseling a) Postnatal Diagnose of more than 2000

genetic diseases b) Premarietal test for 108 recessive disorders c) Prenatal diagnosis from maternal blood d) Preimplantation genetic screen (PGS) e) Preimplantation genetic diagnosis (PGD)

2. Personalized Genomic Health a) Personalized cancer treatment b) Pharmacogenomics c) Nutrigenomics

3. Predictive Genomic (Families) a) Detect and prevent susceptibility to heart

diseases b) Diabetes and obesity c) Detect susceptibility to cancer and initiate

preventative measures 4. Genetic and molecular Consultation services

Dr. Darrol Baker

1. Reports should serve clinicians and patients 2. Reports should be dynamic serve you for life 3. Reports should look attractive

Bioinformatics www.genatak.com

“Exomes on the go” We need funding and help

Bioinformatics www.genatak.com

Data generation and databases www.genatak.com

• Crime against genomics! Extract one info from NGS

and discard or hide the rest!! • Were do you place the ‘one pathogenic data’

International Curated databases : do not reinvent the wheel

-“Insight-group” Lynch syndrome -BIC

• Were do you place the ‘one pathogenic data’ Genomic Medicine Alliance database

Data generation and databases www.genatak.com

• Even in Curated databases: • Errors are high • Assessment using validated

criteria altered classifications for 66% of 12,006 database entries.

• Phenotypes largely lacking • Large number of SNP in our

population NOVEL

Gulf states: Genome Arabia at last www.genatak.com

• Enormous time depth of human habitation (second only to sub-Saharan Africa)

• This nodal geography means that countless peoples have arrived, settled and passed through, creating a very complex palimpsest of Genetic diversity/heterogeneity

• 50% of all marriages are contracted between

first cousins • Genetic homogeneity/useful autozygosity

mapping (Dr. Sultan’s team >50 genes)

• Arabs are not represented in the Human genome project, HapMap, 1000 Genome project

• Rarer variants found only in Arab populations have yet to be discovered

• Greatest blunder against identifying rare variants, important in Diseases (25-30% T2D, PCO, Mendelian inheritance)

Genome Arabia: Rare variants www.genatak.com

• A survey by Bodmer et al., found that: 45% of known rare variants conferred more than a 3-fold risk of disease, whilst 45% of common alleles had odds ratios below 1.2. • Private mutations in PCSK9 (<0.5% frequency) can

change LDL-C by over 100 mg/dl; ~20% frequency allele found by GWAS only changed LDL-C by 3 mg/dl.

• Low frequency and rare variants tend to have

larger effect sizes, are extremely important mediators of complex disease risk.

Qatar National Research Fund

Genome Arabia: Rare variants www.genatak.com

• Data are from Li et al., Behar et al., and Hunter-Zinck et al. Used ~20,000 SNPs which overlapped between the Illumina 650Y and Affymetrix 5 arrays and which allowed unambiguous identification of alleles.

• Need to sample the population well

Genome Arabia www.genatak.com

• In 2012: Set up Genome Arabia working group to whole genome and exome sequence 360 -1000 normal Arabs. Grant funded by QNRF. Prof. Lotfi Chouchane Qatar Weil Cornell Prof. Jim Wilson University of Edinburgh Involvement of (Pan Asian population Genomic Initiative) PAPGI

Genome Arabia www.genatak.com

• Considerable higher proportion of ROH over 5 Mb was observed in the Kuwaiti samples when compared to the Orkney population.

• Over three times as many

Kuwaitis had at least one ROH > 10 Mb in length than Orcadians.

• Indicating recent inbreeding loops in their pedigrees.

Genome Arabia www.genatak.com

EXomes Case1 Case2 Case3 Case4 Case5 Case6 Case7 Case8

Ethnicity Bedouin Bedouin Bedouin Mixed Mixed Syrian KU Mixed

Breeding Inbred Inbred Inbred mother father child

Total variants

139,128 132,863 123,653 102,542 102,337 46,083 44,458 45,253

Novel Variants

13,255 12,540 12,169 10,137 9,969 3,127 3,081 3,084

Novel serious consequences 747 740 744 743 734 670 647 662

Saudi Genome www.genatak.com

Qatar Genome www.genatak.com

Thank you www.genatak.com

We need to Educate that behind the Veil, is a human that is 90-99% identical to any other